Benzothiazepine derivatives

ABSTRACT

BENZOTHIAZEPINE DERIVATIVES OF THE FORMULA:   2-R1,3-(R2-O-),5-(R3-N(-R4)-Y-),X-2,3-DIHYDRO-1,5-   BENZODIAZEPIN-4(5H)-ONE   WHEREIN R1 IS A PHENYL GROUP WHICH MAY BE SUBSTITUTED WITH 1 TO 3 LOWER ALKYL GROUPS, LOWER ALKOXY GROUPS OR HALOGEN ATOMS, R2 IS A HYDROGEN ATOM OR A LOWER ALKANOYL GROUP, R3 AND R4 EACH A LOWER ALKYL GROUP, X IS A HYRDOGEN ATOM OR A HALOGEN ATOM AND Y IS AN ALKYLENE GROUP OF 2 OR 3 CARBON ATOMS, AND THEIR NON-TOXIC ACIDADDITION SALTS. THE COMPOUNDS ARE USEFUL AS ANTIDEPRESSANTS, TRANQUILIZERS AND CORONARY VASODILATORS.

United States Patent 0 3,562,257 BENZOTHIAZEPINE DERIVATIVES HiroshiKngita and Hirozumi Inoue, Tokyo-to, and Mun cyoshi Ikezaki and SatoshiTakeo, Oomiya-shi, Japan, assignors to Tanabe Seiyaku Co., Ltd., Osaka,Japan, a corporation of Japan No Drawing. Filed Oct. 17, 1968, Ser. No.768,550 Claims priority, application Japan, Oct. 28, 1967,

42/69,545, 42/69,546; June 17, 1968, 43/41,789,

Int. Cl. C07d 43/40 US. Cl. 260-2393 43 Claims ABSTRACT OF THEDISCLOSURE Benzothiazepine derivatives of the formula:

X -OR2 N H s I 0 YN wherein R is a phenyl group which may be substitutedwith 1 to 3 lower alkyl groups, lower alkoxy groups or halogen atoms, Ris a hydrogen atom or a lower alkanoyl group, R and R are each a loweralkyl group, X is a hydrogen atom or a halogen atom and Y is an alkylenegroup of 2 or 3 carbon atoms, and their non-toxic acid addition salts.The compounds are useful as antidepressants, tranquilizers and coronaryvasodilators.

This invention relates to novel benzothiazepine derivatives andpreparation thereof.

The said benzothiazepine derivatives are representable by the formula:

wherein R is a phenyl group which may be substituted with 1 to 3 loweralkyl groups (eg. methyl, ethyl, propyl, isopropyl, butyl), lower alkoxygroups (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy) or halogenatoms (e.g. chlorine, bromine), R is a hydrogen atom or a lower alkanoylgroup (e.g. acetyl, propionyl, butyryl), R and R are each a lower alkylgroup (e.g. methyl, ethyl, propyl, isopropyl, butyl), X is a hydrogenatom or a halogen atom (e.g. chlorine, bromine, etc.), and Y is analkylene group of 2 or 3 carbon atoms (e.g. trimethylene, propylene).The term lower used in conjunction with an atomic group is intended tomean one having no more than 8 carbon atoms.

Hitherto, it has been reported that thiazesim (i.e. 2- phenyl-S-(fidimethylamiuoethyl) 2,3 dihydro-1,5- benzothiazepin-4(5H)-one) has anantidepressive action [cf. Freeman et al.: Current Therapeutic Research,7, 655 (1965); Berry et al.: British Journal Psychiat., 114, 203 (1968);Krapcho et al.: J. Medical Chemistry, 9, 191 1966)]. It has now beenfound that the benzothiazepine derivatives [I] have an antidepressiveactivity nearly equal to that of thiazesim but with remarkably lesstoxicity. Particularly, the following compounds are excellentantidepressants compared with thiazesim in respect to the relative ratioof the maximum toxic dose (hereinafter referred to as MTD)(intraperitoneal injection)/antidepressive activity:

2- (4-methylphenyl -3-hydroxy-5-13-dimethylaminoethyl)-2,3-dihydro-1,5benzothiazepin-4(5H)-one(hydrochloride) 2- 4-methoxyphenyl -3-hydroxy-5-(,B-dimethylaminoethyl)-7-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (hydrochloride),

2, (4-chlorophenyl -3-hydroxy-5-B-dimethylaminoethyl)-7-chloro-2,3-dihydro-1,5-benzothiazepin-4- (5H)-one (hydrochloride),

2- (4-methoxyphenyl) -3-hydroxy-5-B-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one(hydrobromide) 2- (4-methoxyp henyl -3 -hydroxy-5-('y-dimethylaminon-propyl)-7-chloro-2,3-dihydro-1,S-benzothiazepin-4(5H) -one (hydrochloride), etc.

It was also ascertained by the rotor-rod test that themotor-coordinating effect of the benzothiazepine derivatives [I] on miceis nil or significantly weaker than that of thiazesim.

Moreover, the benzothiazepine derivatives [I] have a potent tranquilizeraction, some of which are comparable to or better than chlordiazepoxide.Particularly, the following compounds are apparently better thanchlordiazepoxide with respect to the tranquilizer activity and therelative ratio of MTD/tranquilizer activity: 2-(4-methylphenyl) 3-hydroxy-5-(p-dimethylaminoethyl)-2,3-dihydro 1,5 benzothiazepin 4(5H)one (hydrochloride), 2 (4 methoxyphenyl)-3-hydroxy-5-(B-dimethylaminoethyl) 7 chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)- one(hydrochloride), etc. The above described properties are characteristicof the benzothiazepine derivatives [I]. Thiazesim is known to possesssubstantially no tranquilizer action.

Furthermore, the benzothiazepin derivatives [I] show a coronaryvasodilating action stronger than that of papaverine. Some of them, e.g.2-(4 methoxyphenyl)-3- acetoxy 5 (5 dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin 4(5H) one (hydrochloride), exhibit such a high potency asnearly equal to or more than dipyridamole (i.e. 2,6 di[di(2hydroxyethyl)amino]-4,8- dipiperidinopyrimido [5 ,4-d] pyrimidine) Thetoxicity of the benzothiazepine derivatives [-1] is relatively low. Forinstance, the acute toxicity of 2-(4-. methoxyphenyl)-3-acetoxy 5(fl-dimethylaminoethyD- 2,3-dihydro-1,5-benzothiazepin 4(5H) one(hydrochloride) when administered to mice is LD =about 70 mg. /kg.(intravenous route) or about 1000 mgjkg.

(oral route).

Thus, the benzothiazepine derivatives [I] and their non-toxicacid-addition salts are useful as antidepressants, tranquilizers andcoronary vasodilators. Their unit dosages or therapeutically effectivequantities can vary over a Wide range, for instance, from about 0.5 toabout 500 mg. depending on the age of the patient, the degree oftherapeutic effect desired, the kind of therapeutic activity requiredand the like. In general, however, a suitable daily dose of thebenzothiazepine derivative [I] or its non-toxic acid-addition salt forhuman adults may be from about 100 to 400 mg., when used as anantidepressant or a tranquilizer. In cases where its effect as acoronary vasodilator is desired, the dose may be considerably reduced.For instance, the presently most potent compound, i.e.2-(4-methoxyphenyl)-3-acetoxy-5-(pdimethylaminoethyl) 2,3dihydro-l,5-benzothiazepin- 4(5H)-one, is effective for amelioration ofacute or chronic coronary symptom such as coronary insufficiency, anginapectoris or cardiac infarction at a daily dose of about mg. byintravenous route or of about to about 60 mg. by oral route for humanadult. At such doses the paroxysrn of angina pectoris may be preventedeffectively.

According to the present invention, the novel benzothiazepinederivatives [I] can be prepared by reacting an alkali metal salt of thecompound represented by the formula:

X OII H II wherein R and X are each as defined above with an aminoalkylhalide represented by the formula:

a ZYN wherein R R and Y are each as defined above and Z is a halogenatom (e.g. chlorine, bromine) and if desired, acylating in aconventional manner the resultant compound represented by the formula:

wherein R R R, X and Y are each as defined above.

The starting compound [II] is readily obtainable, for instance, bycondensing at an elevated temperature a 2- aminothiophenol which mayhave a halogen atom on the benzene ring, with an epoxyalkanoic ester ofthe formula:

wherein R is as defined above. Preferred examples of the compound [II]are as follows:

2-phenyl-3-hydroxy-2,3-dihydro-1,5-benzothiazepin- 4 (5H) -one,

2- (4-methylphenyl -3-hydroxy-2,3-dihydro-l ,S-benzothiazepin-4( 5H)-one,

2- (4-methoxyphenyl) 3-hydroxy-2,3-dihydro- 1,5-benzothiazepin-4 5 H)-one,

2- 2,4-dimethoxyphenyl -3-hydroxy-2,3-dihydrol ,5-

benzothiazepin-4(5 H) -one,

2- (3 ,4,5-trimethoxyphenyl) -3-hydroxy-2,3-dihydro-1,5-

benzothiazepin-4 5 H -one,

2- (4-chlorophenyl)-3-hydroxy-2,3-dihydro- 1,5-benzothiazepin-4 5 H-one,

2- 2,4-dichlorophenyl -3-hydroxy-2, 3-dihydro-1,5-

benzothiazepin-4 5H -one,

2-phenyl-3-hydroxy-7-chloro-2,B-dihydro-1,5-benzothiazepin-4(5 H -one,

2- (4-methylphenyl -3-hydroxy-7-chloro-2,3-dihydro- 1,5-benzothiazepin-45 H -one,

2- 4-methoxyphenyl) -3-hydroxy-7-chloro-2,3-dihydro-1,5-benzothiazepin-4 5 H -one,

2- 2,4-dimethoxyphenyl -3-hydroxy-7-chloro-2,3-dihydro1,5-benzothiazepin-4 (5H -one,

2- 3,4,5 -trimethoxyphenyl-3-hydroxy-7-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one,

2- 4-chlorophenyl -3-hydroxy-7-chloro-2,3-dihydro- 1,5-benzothiazepin-45H -one,

2- 2,4-dichlorophenyl -3-hydroxy-7-chl0ro-2,3-dihydro-1,5-benzothiazepin-4 5H -one, etc.

Prior to subjecting the compound [II] to the reaction in the process ofthis invention, said compound is converted into its alkali metal salt,for instance, by treating with an alkali metal (e.g. sodium, potassium,etc.); an

' alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.) oran alkali metal amide (e.g. sodium amide, potassium amide, etc.). Thereaction is carried out in a solvent (e.g. dioxane, toluene, xylene,dimethylsulfoxide), usually at a temperature from about 20 to 40 C. forabout an hour.

The alkali metal salt of the compound [II] thus prepared is then reactedwith the aminoalkyl halide [III]. The alkali metal salt which wasproduced in the reaction mixture described above can be used by itselfin the reaction with the aminoalkyl halide or it can be reacted togetherwith the solvent used in the alkali metal salt preparation. The reactionmay be carried out at room temperature but a temperature of about 40 toC. with a reaction time of l to 6 hours is preferred.

The acylation of the compound [Ia] thus produced is an optional step andmay be carried out by a conventional procedure. For instance, thecompound [la], is treated with a lower alkanoic acid (e.g. acetic acid,propionic acid, butyric acid) in the presence of a dehydrating agent(e.g. polyphosphoric acid, phosphoric anhydride, conc. sulfuric acid) orwith a reactive derivative of a lower alkanoic acid such as a loweralkanoic anhydride (e.g. acetic anhydride, propionic anhydride) or alower alkanoyl halide (e.g. acetyl chloride, acetyl bromide, propionylchloride, butyryl chloride, capropyl chloride). When the acylating agentis a lower alkanoyl halide, the presence of a base (e.g. pyridine,triethylamine, dimethylaniline) in the reaction system is preferred. Theacylation is normally effected at room temperature or elevatedtemperature for a sufficient period of time. The resulting product inthe acylation is represented by the formula:

wherein R R R X and Y are each as defined above and R is a loweralkanoyl group (e.g. acetyl, propionyl, butyryl, etc.).

The thus obtained benzothiazepine derivative [I], i.e. the compound [Ia]or the compound [Ib], can be converted into its acid-addition salts bytreatment with an organic or inorganic acid (e.g. acetic acid, oxalicacid, malonic acid, tartaric acid, malic acid, citric acid, lactic acid,gluconic acid, aspartic acid, hydrochloric acid, hy-

drobromic acid, sulfuric acid, nitric acid, perchloric acid) in asuitable solvent (e.g. water, methanol, ethanol).

For medicinal purposes the benzothiazepine derivatives [I] and theirnon-toxic acid-addition salts may be employed in the form ofpharmaceutical preparations, which contain them in admixture with apharmaceutical organic or inorganic carrier material suitable forenteral or parenteral applications. Oral administration by the use oftablets, capsules, powders or in liquid form such as suspensions,solutions, emulsions or syrups is particularly advantageous. When formedinto tablets, conventional excipients (e.g. sodium citrate, lactose,microcrystalline cellulose, starch), lubricating agents (e.g. anhydroussilicic acid, hydrized castor oil, magnesium stearate, sodium laurylsulfate, talc) and binding agents (e.g. starch paste, glucose, lactose,gum acacia, gelatin, mannitol, magnesium trisilicate, talc) can be used.When administered as liquids, conventional liquid carriers can beemployed. In the case of solid preparations, each unit dosage form ofthe active ingredient can contain from about 5 to 95% of same by weightbased on the entire composition with the remainder comprisingconventional pharmaceutical carriers. When the therapeutic agent is usedas an aqueous solution, i.e. injection, the solution may contain about0.05 to 0.5% of same by weight based on the entire solution.

Practical and presently-preferred embodiments of the present inventionare illustratively shown in the following examples.

EXAMPLE 1 0.6 g. of 43.9% sodium hydride was added to 13 ml. ofdimethylsulfoxide and the resulting mixture was stirred for an hour at60 C. under nitrogen atmosphere. After the addition of 0.9 g. of2-(4-chlorophenyl)-3-hydroxy- 2,3-dihydro-1,5-benzothiazepin-4(5H) one,the resultant mixture was stirred for an hour at room temperature.

A solution of 0.5 g. of ,B-dimethylaminoethyl chloride in 3 ml. ofdimethylsulfoxide was added dropwise to the mixture, and the resultingmixture was heated at 60 C. for an hour. The reaction mixture was thenpoured into ice water and extracted with ether. The ethereal layer wasextracted with hydrochloric acid. The aqueous layer was made alkalinewith potassium carbonate and once again extracted with ether. The etherlayer was dried and evaporated to remove other thereby producing 0.76 g.of crystals. After recrystallization of the crystals (from ethanol, 0.65g. of 2-(4-chlorophenyl) 3 -hydroxy-5-(B-dimethylaminoethyl) 2,3 dihydro1,5 benzothiazepin- 4(5H)-one was obtained having a melting point from10 8 to 110 C. The product was dissolved in ether and hydrogen chloridegas was bubbled into the solution. The resultant hydrochloride wasrecrystallized from ethanol whereby crystals with a melting point from215 to 217 C. were obtained.

' EXAMPLE 2 0.6 g. of 43.9% sodium hydride was added to 13 ml. ofdimethylsulfoxide and the resulting mixture was stirred for an hour at60 C. under nitrogen atmosphere. After the addition of 1.5 g. of2-('4-methylphenyl)3-hydroxy-2,3-dihydro 1,5 benzothiazepin 4(5H)-one atroom temperature, the mixture was stirred at the same temperature for anhour.

A solution of 0.74 g. of S-dimethylaminoethyl chloride in 3 ml. ofdirnethylsulfoxide was added dropwise to the resulting mixture. Themixture was then heated at 50 C. for 50 minutes. The reaction mixturewas treated as in Example 1 thereby producing 1.68 g. of2-(4-methylphenyl) 3 -hydroxy 5 8 dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one as an oil. The oil was dissolved inether and hydrogen chloride gas was bubbled into the solution. Theresultant hydrochloride was recrystallized from methanol whereby 1.13 g.of crystals, having a melting point from 238 to 241 C., was obtained.

6 EXAMPLE 3 0.6 g. of 2-(4-methoxyphenyl)-3-hydroxy-7-chloro-2,3-dihydro-1,5-benzothiazepin 4(5H) -one was added at room temperature to areaction mixture of 98 mg. of 43.9% sodium hydride and 10 ml. ofdimethylsulfoxide. After stirring at room temperature for 30 minutes, asolution of 0.23 g. of fi-dimethylaminoethyl chloride in 2 ml. ofdimethylsulfoxide was added dropwise to the mixture and the resultantmixture was heatedfor 1.5 hours at 45 to 50 C. The reaction mixture wastreated as in Example 1 thereby producing 550 mg. of crude free base of2-(4- methoxyphenyl)-3-hydroxy 5 (B-dimethylaminoethyl): 7-chloro 2,3dihydro 1,5-benzothiazepin-4(5H)-one.

The base was crystallized by adding a small quantity of ether, and theresultant crystals were collected by filtration to give 320 mg. of thefree base having amelting point from to 147 C. The free base wasconverted into its hydrochloride as in Example 1. When recrystallizedfrom ethanol 310 mg. of the hydrochloride as crystals were obtainedhaving a melting point from 217 to 220 C.

EXAMPLE 4 1.5 g. of 2-(4-chlorophenyl) 3 hydroxy-7-chloro-2,3-

r dihydro-1,5-benzothiazepin-4(5H)-one was added to the reaction mixtureof 0.24 g. of 43.9% sodium hydride and 15 ml. of dimethylsulfoxide atroom temperature. After stirring at room temperature for one hour, asolution of 0.61 g. of B-dimethylaminoethyl chloride in 3 ml. ofdimethylsulfoxide was added dropwise to the mixture and then heated at50 C. for an hour. The reaction mixture was treated as in Example 1thereby producing 1.24 g. of 2-(4-chlorophenyl) 3hydroxy-5-(,B-dimethylaminoethyl) 7 chloro 2,3dihydro-1,5-benzothiazepin 4 (5H)-one hydrochloride. Melting point 194to 197 C. (recrystallized from a mixture of ethanol and ether).

In the same manner as described in Example 1, the following compoundswere obtained: 2-(3,4,5 trimethoxyphenyl) 3hydroxy-5(,B-dimethylaminoethyl) 7-chloro-2,3-dihydro 1,5 benzothiazepin4(5H) one perchlorate, melting point 145 to C. (recrystallized fromethanol); 2-(4-methylphenyl) 3 hydroxy-5(fl-dimethylaminoethyl) 7 chloro2,3 dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, melting point178 to 180 C. (recrystallized from ethanol); 2-(2,4-dichlorophenyl) 3hydroxy 5 (fit-dimethylaminoethyl)-7 chloro 2,3 dihydro 1,5benzothiazepin-4(5H)-one hydrochloride, melting point 217 to 219 C.(recrystallized from ethanol), etc.

EXAMPLE 5 0.3 g. of 43.9% sodium hydride was added to a solution of 1.5g. of 2-phenyl-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)'-one in 25ml. of dioxane, at 25 C. The mixture was stirred at the room temperaturefor one hour and at about 40 C. for 30 minutes. A solution of 0.87 g. of,B-dimethylaminoethyl chloride in 5 ml. of dioxane was added dropwise tothe mixture at 20 C. The resultant mixture was then stirred at 55 to 65C. for 5 hours. The reaction mixture was evaporated under reducedpressure to remove the solvent. The residue was dissolved in chloroformand extracted with 10% hydrochloric acid. The aqueous layer was madealkaline with potassium carbonate and extracted with ether. The ethereallayer was washed with water, dried and evaporated to remove etherthereby producing 500 mg. of crystals, which were recrystallized fromethanol to give 460 mg. of 2- phenyl 3 hydroxy 5(B-dimethylaminoethyl)-2,3-dihydro 1,5 benzothiazepin-4(5H)-one having amelting point from 123 to 124 C. Hydrochloride, melting point 215 to 218C. (recrystallized from ethanol).

EXAMPLE 6 0.55 g. of 43.9% sodium hydride was added to a solution of 3.0g. of 2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro 1,5benzothiazepin-4(5H)-one in 60 ml. of dioxane, at room temperature. Themixture was stirred at room temperature for 1.5 hours. A solution of1.46 g. of {B-dimethylaminoethyl chloride in 8 ml. of dioxane was addeddropwise to the mixture at C. and then stirred for 6 hours at 60 C. Thereaction mixture was treated as described in Example 5. The resultantcrystals were recrystallized from ethanol to give 0.46 g. of2-(4-methoxyphenyl) 3 hydroxy 5 (fl-dimethylaminoethyl) 2,3-dihydro-1,S-benzothiazepin-4(5H)one, having a melting point from 105 to107 C. Hydrochloride, melting point 225 to 228 C. (recrystallized fromethanol).

In the same manner as described in Example 5, the following compoundswere obtained: 2-(3,4-dimethoxyphenyl) 3 hydroxy 5(B-dimethylaminoethyD-Z,3-dihydro 1,5 benzothiazepin 4(5H)-onehydrochloride, melting point 149 to 151 C. (recrystallized fromethanol); 2-(3,4,S-trimethoxyphenyl) 3 hydroxy 5 (fl-dimethylaminoethyl)2,3 dihydro 1,5 benzothiazepin-4(5H)- one hydrobromide, melting point179 to 180 C. (recrystallized from a mixture of ethanol and ether);2-(2,4- dichlorophenyl) 3 hydroxy 5 (fl-dimethylaminoethyl) 2,3 dihydro1,5 benzothiazepin 4(5H) one hydrochloride, melting point 215 to 217 C.(recrystallized from ethanol);2-phenyl-3-hydroxy-5-(,B-dimethylaminoethyl) 7 chloro 2,3 dihydro 1,5benzothiazepin- 4(5H)-one hydrochloride, melting point 228 to 230 C.(recrystallized from methanol); 2 (3,4 dimethoxyphenyl) 3 hydroxy 5(p-dimethylaminoethyl) 7- chloro 2,3 dihydro 1,5 benzothiazepin 4(5H)one hydrochloride, melting point 154 .to 156 C. (recrystallized fromethanol), etc.

EXAMPLE 7 A mixture of 0.6 g. of 43.9% sodium hydride and ml.' ofdimethylsulfoxide was stirred for one hour at 60 C. under nitrogenatmosphere. 3 g. of 2-phenyl-3-hydroxy 2,3-dihydro 1,5benzothiazepin-4(5H)-one was added to the mixture at room temperatureand stirred for one hour at 25 to 28 C. A solution of 1.75 g. of-dimethylamino-n-propyl chloride in 5 ml. of dimethylsulfoxide was addeddropwise to the mixture, and the mixture was then heated at 50 to 53 C.for 70 minutes. The reaction mixture was then poured into ice water andextracted with chloroform. The chloroform layer was extracted with 10%hydrochloric acid. The aqueous layer was made alkaline with potassiumcarbonate and extracted again with chloroform. The chloroform layer wasdried and evaporated to remove the solvent producing 3.0 g. of2-phenyl-3-hydroxy- 5-('y-dimethylamino-n-propyl) 2,3 dihydro 1,5benzothiazepin-4(5H)-one having a melting point at 103 to 104 C. Theproduct was dissolved in ether and hydrogen chloride gas was bubbledinto the solution. The resulting hydrochloride was recrystallized fromethanol to give crystals having a melting point at 198 to 199 C.

In the same manner as described in Example 7, the following compoundswere obtained: 2 (4 methoxyphenyl) 3 hydroxy 5('y-dimethylamino-n-propyl)- 2,3 dihydro 1,5 benzothiazepin-4(5H)-onehydrochloride, melting point 151 to 156 C. (recrystallized from amixture of ethanol and ether); 2-(3,4,5-trimethoxyphenyl) 3hydroxy-5-('y-dimethylamino-n-propyl) 2,3 dihydro 1,5benzothiazepin-4(5H)-one hydrochloride, melting point 187 to 188 C.(recrystallized from a mixture of ethanol and acetone);2-(4-methylphenyl) 3 hydroxy 5 -dimethylamino-n-propyl)- 2,3 dihydro 1,5benzothiazepin-4(5H)-one hydrochloride, melting point 212 to 213 C.(recrystallized from ethanol); 2-phenyl 3 hydroxy 5(q-dimethylaminon-propyl) 7 chloro 2,3 dihydro 1,5benzothiazepin-4(5H)-one oxalate, melting point 126 to 128 C.(recrystallized from a mixture of methanol and ethanol);2-(4-chlorophenyl) 3 hydroxy 5 ('y-dimethylaminon-propyl) 7 chloro 2,3dihydro 1,5 benzothiaze- 8 pin 4(5H) one hydrochloride, melting point229.5 to 230.5 C. (recrystallized from ethanol); 2-(4-methoxyphenyl) 3hydroxy 5 (a-methyl-B-dimethylaminoethyl) 2,3 dihydro 1,5benzothiazepin-4(5H)-one oxalate, melting point 189 to 190 C.(recrystallized from ethanol), etc.

EXAMPLE 8 A mixture of 0.65 g. of 43.9% sodium hydride and 40 ml. ofdimethylsulfoxide was stirred at 60 C. for an hour under nitrogenatmosphere, and 4 g. of 2-(4- methoxyphenyl) 3hydroxy-7-chloro-2,3-dihydro-1,5- benzothiazepin-4(5H)-one were thenadded at room temperature. The resulting mixture was stirred at roomtemperature for 40 minutes and then at 40 to 45 C. for 20 minutes. Asolution of 1.88 g. of y-dimethylamino-npropyl chloride in 5 ml. ofdimethyl-sulfoxide was added dropwise to the mixture followed bystirring at room temperature for one hour and at to C. for one hour. Thereaction mixture was treated as described in Example 7 producing 4.4 g.of crude free base of 2-(4-methoxyphenyl) 3 hydroxy-54ydimethylamino-n-propyl)-7- chloro-2,3-dihydro-1,5-benzothiazepin4(5H)-one as a viscous substance. The product was dissolved in ether andhydrogen chloride gas was bubbled into the solution. The resultinghydrochloride was recrystallized from a mixture of ethanol and ether togive 3.56 g. of crystals having a melting point from 221 to 225 C.

EXAMPLE 9 A mixture of 2 g. of2-phenyl-3-hydroxy-5-(B-dimethylaminoethyl)-2,3-dihydro-l,5-benzothiazepin-4(5H)one and 20 ml. of acetic anhydride was heated on a water bath for 4hours. The reaction mixture was evaporated under reduced pressure toremove acetic anhydride. The

residue was mixed with ice water and made alkaline with sodiumbicarbonate. The precipitated crystals were collected by filtration toobtain 2.0 g. of 2-phenyl-3-acetoxy- S-(fi-dimethylaminoethyl) 2,3dihydro-1,5-benzothiazepin-4(5H)-one. Hydrobromide, melting point 215 to217 C. (recrystallized from a mixture of ethanol and acetone).

EXAMPLE 10 0.6 g. of caproyl chloride was added while stirring undercooling to a solution of 1.4 g. of 2-phenyl-3-hydroxy-S(fl-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 5ml. of pyridine. After preser vation for 2 days in a refrigerator, thereaction mixture was poured into ice water and extracted withchloroform. The chloroform layer was washed with water, dried andevaporated to remove the solvent. The residue was dissolved in ethanoland perchloric acid was added thereto. The precipitate was collected byfiltration and recrystallized from ethanol to give 550 mg. of 2-phenyl-3-pentylcarbonyloxy S-(fl-dimethylaminoethyD-2,3-dihydro-1,5-benzothiazepin 4(5H) one perchlorate having a meltingpoint from 137 to 139 C. (recrystallized from ethanol).

EXAMPLE 11 A mixture of 1.5 g. of2-(4-methoxyphenyl)-3-hydroxy-5-(B-dimethylaminoethyl)2,3-dihydro-l,5-benzothiazepin-4-(5H)-one and 20 ml. of acetic anhydridewas heated on a water bath for 5 hours. The reaction mixture wasevaporated under reduced pressure to remove acetic anhydride and theconcentrated product was poured into ice water. The resulting mixturewas made alkaline with sodium bicarbonate and extracted with chloroform.The chloroform layer was dried and evaporated to remove the solvent. Theresidue was dissolved in acetone, and an ethanol solution containinghydrogen chloride was added thereto producing 1.53 g. of2-(4-methoxyphenyl)- 3-acetoxy-5-(fl-dimethylaminoethyl) 2,3dihydro-1,5- benzothiazepin-4(5H)-one hydrochloride having a meltingpoint from 187 to 188 C. When recrystallized from a mixture of ethanoland ether, the melting point was raised to 187.5 to 188.5 C.

In the same manner as described in Example 11, the following compoundsWere obtained: 2-(3,4,S-trimethoxyphenyl)-3-acetoxy 5(B-dimethylaminoethyl)-2,3-dihytoxy-S-('y-dimethylamino-n-propyl)-2,3dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, melting point 136 to139 C. (recrystallized from a mixture of acetone and ether);2-phenyl-3-acetoxy 5('y-dimethylamino-n-propyl)-7-chloro-2,3-dihydro-1,5-benzothiazepin 4(5H)-one dro-1,5-benzothiazepin-4-(5H)-one oxalate, melting point 5hydrochloride, melting point 159 to 161 C. (recrystal- 117 to 119 C.(recrystallized from a mixture of ethanol lizcd from a mixture ofethanol and ether); 2-(4-rnethoxyand ether);2-(4-rnethylphenyl)-3-acetoxy-5-(B-dimethylphcnyl)-3-acetoxy-5(y-dimethylamino n propyl)-7- aminoethyl)-2,3-dihydro1,5-benzothiazepin-4(5H)-one chloro-2,3-dihydro-1,5-benzothiazepin4(5H)-one hydrohydrochloride, melting point 213 to 214 C. (recrystal- 1Ochloride, melting point 169 to 170 C. (decomp.) (re li d f a i t of thnol nd ether); 4-phenyl-3- crystallized from a mixture of ethanol,acetone and ether); acetoxy-S-(fi-dimethylaminoethyl)-7-chloro2,3-dihydro- -c 1 P y Y (vy 1,5-benzothiazepin 4(5H one hydrochloride,melting propyl)-7-chloro-2,3 dihydro-1,5-benzothiaze in-4 5-H n e I v ep point 199 to 200 C. (recrystallized from a mixture of e ydrochloride,melting point 155 to 160 C. (reethanol and ether); 2-(4-methoxyphenyl)3-acetoxy-5- crystallized from a mixture of ethanol, acetone and(,6-dimethylaminoethyl)-7-chloro-2,3 dihydro-1,5-benzoether), etc.thiazepin-4(5H)-one hydrochloride, melting point 162 to EXAMPLE 13 167C. (recrystallized from a mixture of ethanol and 0 7 f ether);2-(4-chlorophenyl) 3-acetoxy-5-(;3-dimethylamiproplonill .chlorflde wasadded Whlle Surfing noethyl) 7 chloro 2,3 dihydro-1,5-benzothiazePin- 2Off fi so mono 4(5H)-one hydrochloride, melting point 156 to 158 c. fi gg g j g gg fi fg fiffig f i i g $9 3. ll'df 't h adth t. rslrlg(recrysta lze mm a mlX me of et anol n 6 6 c for 2 hours, 0.3 g. ofpropionyl chloride was added, and EXAMPLE 12 the resultant mixture waspreserved in a refrigerator for A mixture of 1.5 g of p y y y (Tigdho-urs. The reaction mixture was poured into ice Water extracted withchloroform. The chloroform layer 'was methylamino-n-propyl)-2,3-dihydro1,5-benzoth1azep1nd ried and evaporated to remove the solvent. 2.17 g.of the 4(5H)-one and 20 ml. of acetic anhydride was heated resum b t 1 dd on a water bath for 5 hours The reaction mixture was Hg lscous SH s21110-e was 1850 V6 m acetone an 0.85 g. of methanesulfonic acid wasadded thereto. The evaporated under reduced pressure to remove acetican- I precipitate was collected and recrystallized from a mixturehydride and water was added thereto. The resulting mixof acetone andethyl acetate to give 0.74 g. of 2-phenylture was made alkaline withsodium bicarbonate and extr cted with hloroform The chloroform 1a er wasdried 3prop1onyloxy5'('y-dlmethylammo'n'propyl)'23 dlhy' c ydro-1,5-benzothiazepin-4(5H)-one methanesulfonate havand evaporated toremove the solvent. 1.67 g. of the reing a melting Point from 132 to 133C i gf g g xg gf i i g iigi gg a The antidepressive activity of thebenzothiazepin derivg :2 mixture 1 53 g 1 3 acetoX g? ati'ves [I]obtained in the above examples was evaluated (TdimethYlamino n pfipgq)-23 dilflydril s be bly the depressive effect on septal-lesioned ratsand is azepin-4 (5H)-one hydrochloride was obtained as prisms 2323 12112 maximum toxic dose the g g g z g g (recrystalhzed from mlxture Thetranquilizer activity of the benzothiazepin deriva- In the same manneras described in Example 12 the tives:l [I] was evaluated by thefighting-mouse method Te es h' t 1.: J. Pha lo & E following compoundswere obtained: 2-(4-methylphenyl)- g g gii ii ifi gfig gi Them Y- y Thecoronary vasodilating activity of the benzothiazepin 15 -benZ0th1aZeP1I1one Y melting derivatives [I] -was evaluated by the Langendorff methodPoint 203 2045 (recrystalllzed from a mlxtule 0f 40 using isolatedhearts of guinea pigs and the coronary flowethanol and ether); 2-(3,4,5trimethoxyphenyl)3-aceincreasing eflect on dogs and is shown in Table 3.

TABLE 1 ED MTD Test compound-Formula R1 R2 X Y (mg/kg.) mgJkg.) MTD/EDW4-ch1orophenyl H H 42.04 238 4-methylphenyl H H 35.35 300 8.44-methoxyphenyl H 01 22.92 100 4. 36 i'tiitl23.% lf a a 22 5288 l g i,4-dtilc1hlorogl 1enyl g1 120.22 300 2. 50 R1 3, l inlm "yifitir ij:ijjjjH H 2'29? i38 ca. i328 /S 3, li),tiigirlnethoxy- H H 62.5 100 ca. 1.602,4-dicl ilarophenyl H H 62.5 100 ca. 1.60 OR2 1;? fi-dinliethoxypheny E16111 (CdH) 4225i ca. en X \N 3,4,fi rimetlioxyphenyLfl H H Same"? ca.37.9 50 ca. 1.32 'g f' enyl g ig-g 2g 2% I1 .1 t. 4-met l ioxyphenyL HCl 22.27 100 ca 4.49 CH 4-elilorophenyl H 01 37.9 100 ca. 2. 64 3dinethoxyplienyl- H H 113.8 300 ca. 263 i fiftlaysttryi 85288 it (0112)?5 32 183 ca 5"? i-meth i hen Lf 011500 H 7518 100 ca: 1:32 34-methoxyphenyl. CHQCO Cl 50.0 100 ca. 2.00

4chlorophenyl. 1Gil ca. ll C3,.

2 3 8 a a 2a 4-ni t h0xyphenyl:::::: ornco 01 do ca: 2510 100 32.1 4100Phenyl O5H11CO H (CH2)2 ca. 120.2 300 ca. 2.50

Thiazesim 27. 51 30 1. 09

NOTE .Each of the test compounds was administered to septal-lesionedrats (Wister-male; body weight, about 200 g.) by intraperitonealinjection of one ml. per 100 g. body weight of the solution prepared bydissolving the compound into saline solution or 0.5% aqueous solution ofearboxymethylcellulose. The tabulated value of ED5u is the mostefieotive one found within 2 hours after administration of the compound.

TABLE 2 EDao MTD MTD Test compound Formula R R X Y (mg/kg.) (mg/kg.) ED

R 4-chloropl1enyl H H (CH2) 100 ca. 2. 64 4-methylphenyl H II Same asabove 300 7. 85 S 4-methoxyphenyl H Cl 100 4. 153,4,5-trimethoxypl1cnyl. H 300 2. 79 4-0 300 3. 68 -O R 2,4dichloropheny 300 3. 68 X 4-methoxyphenyl 300 ca. 2. 40 ."d 300 ca. 2.64 N- Phenyl. Cl -(CH2)2 ca. 37.9 100 ca. 2. 64 I d 01 cr12)3 ea. 37. 9100 ca. 2. 64 l /CI'I3 YN Ohlordiazepoxide 45. 10 100 2. 2g ThiaZesirn 1Inactive.

NOTE.The activity was evaluated 30 minutes after intraperitonealinjection of the test compound.

TABLE 3 Potency Test compoundFonnula R It X Y ratio R1 S 4-methy1phenylH (CH g' tmethoxyphenyl 1- Same ..-do ....do- .do-. -(CHz)a do. Same X-...do 1-1 H -CH(C1I )CII N; Plienyl 011300... 11 (0Il 4methoxyphenyl-Same H Same. 0 4-methylphenyl do H d 011 Phenyl. do 01 I -methoxyphenyldo- Cl YN ichlorophenyL.-. .do. C l-mcthylphenyl .do H

Thiazesim Dipyridamole Papaverine Firstly increase coronary flow butthen reverse to decrease.

What is claimeclis: 1. A benzothiazepine derivative of the formula:

wherein R is a phenyl group which may be substituted with 1 to 3 loweralkyl groups, lower alkoxy groups or halogen atoms, R is a hydrogen atomor a lower alkanoyl group, R and R are each a lower alkyl group, X is ahydrogen atom or a halogen atom and Y is an alkylene group of 2 or 3carbon atoms, or its non-toxic pharamaceutically acceptable acidaddition salt.

2. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkylphenyl, R is hydrogen, R and R are each lower alkyl, X is hydrogenand Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

3. The benzothiazepine derivative of claim 2, wherein R is4-methylphenyl, R is hydrogen, R and R are each methyl, X is hydrogenand Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

4. The benzothiazepine derivative of claim 1, wherein R is 4-lo-weralkoxyphenyl, R is hydrogen, R and R are each lower alkyl, X is hydrogenand Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

5. The benzothiazepine derivative of claim 1, wherein R is4-methoxyphenyl, R is hydrogen, R and R are are each methyl, X ishydrogen and Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

6. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkoxyphenyl, R is hydrogen, R and R are each lower alkyl, X is 7-haloand Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

7. The benzothiazepine derivative of claim 6, wherein R is4-methoxyphenyl, R is hydrogen, R and R are each methyl, X is 7-chloroand Y is ethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

8. The benzothiazepine derivative of claim 1, wherein R is3,4-di(lower)alkoxyphenyl, R is hydrogen, R and R are each lower alkyl,X is hydrogen and Y is ethylene or its non-toxic pharmaceuticallyacceptable acid-addition salt. a

9. The benzothiazepine derivative of claim 1, wherein R is3,4-di-(lower)alkoxyphenyl, R is hydrogen, R and R are each lower alkyl,X is 7-halo and Y is ethylene or its non-toxic pharmaceuticallyacceptable acid-addition salt.

10. The benzothiazepine derivative of claim 1, wherein R is3,4,5-tri(lo.wer)alkoxyphenyl, R is hydrogen, R and R are each loweralkyl, X is hydrogen and Y is ethylene or its non-toxic pharmaceuticallyacceptable acid-addition salt.

11. The benzothiazepine derivative of claim 1, wherein R is3,4,5-tri(lower)alkoxyphenyl, R is hydrogen, R and R are each loweralkyl, X is 7-halo and Y is ethylene or its non-toxic pharmaceuticallyacceptable acid-addition salt.

12. The benzothiazepine derivative of claim 1, wherein R is4-halophenyl, R is hydrogen, R and R are each lower alkyl, X is hydrogenand Y is ethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

13. The benzothiazepine derivative of claim 1, wherein R is4-halophenyl, R is hydrogen, R and R are each lower alkyl, X is 7-haloand Y is ethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

14. The benzothiazepine derivative of claim 13, wherein R is2,4-dihalophenyl, R is hydrogen, R and R are each methyl, X is 7-ch1oroand Y is ethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

15. The benzothiazepine derivative of claim 1, wherein R is2-4-dihalophenyl, R is hydrogen, R and R are each lower alkyl, X ishydrogen and Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

16. The benzothiazepine derivative of claim 1, wherein R is2,4-dihalophenyl, R is hydrogen, R and R are each lower alkyl, X is7-halo and Y is ethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

17. The benzothiazepine derivative of claim 16, wherein R is2,4-dichlorophenyl, R is hydrogen, R and R are each methyl, X is7-chloro and Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

18. The benzothiazepine derivative of claim 1, wherein R is phenyl, R ishydrogen, R ad R are each lower alkyl, X is hydrogen and Y istrimethylene or its nontoxic pharmaceutically acceptable acid-additionsalt.

19. The benzothiazepine derivative of claim 1, wherein R is phenyl, R ishydrogen, R and R are each lower alkyl, X is 7-halo and Y istrimethylene or its non-toxic pharmaceutically acceptable acid-additionsalt.

20. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkylphenyl, R is hydrogen, R and R are each lower alkyl, X is hydrogenand Y is trimethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

21. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkoxyphenyl, R is hydrogen, R and R are each lower alkyl, X is hydrogenand Y is trimethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

22. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkoxyphenyl, R is hydrogen, R and R are each lower alkyl, X is 7-haloand Y is trimethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

23. The benzothiazepine derivative of claim 1, wherein R is4-methoxyphenyl, R is hydrogen, R and R are each methyl, X is 7-chloroand Y is trimethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

24. The benzothiazepine derivative of claim 1, wherein 'R is3,4,5-tri(lower)alkoxyphenyl, R is hydrogen, R and R are each loweralkyl, X is hydrogen and Y is trimethylene or its non-toxicpharmaceutically acceptable acid-addition salt.

25. The benzothiazepine derivative of claim 1, wherein R is4-halophenyl, R is hydrogen, R and R are each lower alkyl, X is 7-haloand Y is trimethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

26. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkoxyphenyl, R is hydrogen, R and R are each lower alkyl, X is hydrogenand Y is propylene or its non-toxic pharmaceutically acceptableacid-addition salt.

27. The benzothiazepine derivative of claim 1, wherein R is phenyl, R islower alkanoyl R and R are each lower alkyl, X is hydrogen and Y isethylene or its nontoxic pharmaceutically acceptable acid-addition salt.

28. The benzothiazepine derivative of claim 27, wherein R is phenyl, Ris acetyl, R and R are each methyl, X is hydrogen and Y is ethylene orits non-toxic pharmaceutically acceptable acid-addition salt.

29. The benzothiazepine derivative of claim 1, wherein R is phenyl, R islower alkonoyl, R and R are each lower alkyl, X is 7-chloro and Y isethylene or its nontoxic pharmaceutically acceptable acid-addition salt.

30. The benzothiazepine derivative of claim 29, wherein R is phenyl, Ris acetyl, R and R are each methyl, X is 7-chloro and Y is ethylene orits non-toxic pharmaceutically acceptable acid-addition salt.

31. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkylphenyl, R is lower alkanoyl, R and R are each lower alkyl, X ishydrogen and Y is ethylene or its non-toxic pharmaceutically acceptableacidaddition salt.

32. The benzothiazepine derivative of claim 31, wherein R is4-methylphenyl, R is acetyl, R and R are each methyl, X is hydrogen andY is ethylene or its nontoxicpharmaceutically acceptable acid-additionsalt.

33. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkoxyphenyl, R is lower alkanoyl, R and R are each lower alkyl, X ishydrogen and Y is ethylene or its non-toxic pharmaceutically acceptableacidaddition salt.

34. The benzothiazepine derivative of claim 33, wherein R is4-methoxyphenyl, R is acetyl, R and R are each methyl, X is hydrogen andY is ethylene or its nontoxic pharmaceutically acceptable acid-additionsalt.

35. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkoxyphenyl, R is lower alkanoyl, R and R are each lower alkyl, X is7-halo and Y is ethylene or its non-toxic pharmaceutically acceptableacid-addition salt.

36. The benzothiazepine derivative of claim 35, wherein R is4-methoxyphenyl, R is acetyl, R and R are each methyl, X is 7-chloro andY is ethylene or its non-toxic pharmaceutically acceptable acid-additionsalt.

37. The benzothiazepine derivative of claim 1, wherein R is4-halophenyl, R is lower alkanoyl, R and R are each lower alkyl, X is7-halo and Y is ethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

38. The benzothiazepine derivative of claim 1, wherein R is phenyl, R islower alkanoyl, R and R are each lower alkyl, X is hydrogen and Y istrimethylene or its non-toxic pharmaceutically acceptable acid-additionsalt.

39. The benzothiazepine derivative of claim 38, wherein R is phenyl, Ris acetyl, R and R are each methyl, X is hydrogen and Y is trimethyleneor its non-toxic pharmaceutically acceptable acid-addition salt.

40. The benzothiazepine derivative of claim 1, wherein R is phenyl, R islower alkanoyl, R and R are each lower alkyl, X is 7-halo and Y istrimethylene or its non-toxic pharmaceutically acceptable acid-additionsalt.

41. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkylphenyl, R is lower alkanoyl, R and R are each lower alkyl, X ishydrogen and Y is trimethylene or its non-toxic pharmaceuticallyacceptable acid-addition salt.

42. The benzothiazepine derivative of claim 1, wherein R is 4-loweralkoxyphenyl, R is lower alkanoyl, R and R are each lower alkyl, X is7-halo and Y is trimethylene or its non-toxic pharmaceuticallyacceptable acid-addition salt.

43. The benzothiazepine derivative of claim 42, wherein R is4-methoxyphenyl, R is acetyl, R and R are each methyl, X is 7-chloro andY is trimethylene or its nontoxic pharmaceutically acceptableacid-addition salt.

References Cited UNITED STATES PATENTS 3,075,967 l/l963 Krapcho 260239.33,429,874 2/ 1969 Topliss 260239.3 3,445,458 5/1969 Bell 260-239.3

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner U.S. Cl.X.R.

